Background and ObjectivesPatients with acute ischemic stroke due to large vessel occlusion (LVO) deemed eligible for endovascular thrombectomy (EVT) are transferred from the emergency room to the... Show moreBackground and ObjectivesPatients with acute ischemic stroke due to large vessel occlusion (LVO) deemed eligible for endovascular thrombectomy (EVT) are transferred from the emergency room to the angiography suite to undergo the procedure. Recently, the strategy of direct transfer of patients with suspected LVO to the angiography suite (DTAS) has been shown to improve functional outcomes. This study aims to evaluate the cost-effectiveness of the DTAS strategy vs initial transfer of patients with suspected LVO (Rapid Arterial Occlusion Evaluation score >4 and NIH Stroke Scale >10) to the emergency room (ITER).MethodsA decision-analytic Markov model was developed to estimate the cost-effectiveness of the DTAS strategy vs the ITER strategy from a Dutch health care perspective with a 10-year time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) using Dutch thresholds of $59,135 (€50,000) and $94,616 (€80,000) per quality-adjusted life year (QALY). Uncertainty of input parameters was assessed using 1-way sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis.ResultsThe DTAS strategy yielded 0.65 additional QALYs at an additional $16,089, resulting in an ICER of $24,925/QALY compared with the ITER strategy. The ICER varied from $27,169 to $38,325/QALY across different scenarios. The probabilistic sensitivity analysis showed that the DTAS strategy had a 91.8% and 97.0% likelihood of being cost-effective at a decision threshold of $59,135/QALY and $94,616/QALY, respectively.DiscussionThe cost-effectiveness of the DTAS strategy over ITER is robust for patients with suspected LVO. Together with recently published clinical results, this means that implementation of the DTAS strategy may be considered to improve the workflow and outcome of EVT. Show less
Background and ObjectivesScreening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives(FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether... Show moreBackground and ObjectivesScreening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives(FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening isalso effective for FDRs of patients with UIA is unknown. We determined the yield of screening insuch FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, iden-tified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL).MethodsIn this prospective cohort study, we included FDRs, aged 20–70 years, of patients with UIAwithout a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 partici-pating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magneticresonance angiography between 2017 and 2021. We determined UIA prevalence and developed aprediction model for UIA risk at screening using multivariable logistic regression. QoL wasevaluated with questionnaires 6 times during the first year after screening and assessed with alinear mixed-effects model.ResultsWe detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI3.2–7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2–4 mm), and themedian 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%–0.9%). AllUIAs received follow-up imaging, and none were treated preventively. After a median follow-up of24 months (IQR 13–38 months), no UIA had changed. Predicted UIA risk at screening rangedbetween 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcoholconsumption (c-statistic: 0.76; 95% CI 0.65–0.88). At all survey moments, health-related QoLand emotional functioning were comparable with those in a reference group from the generalpopulation. One FDR with a positive screening result expressed regret about screening.DiscussionBased on the current data, we do not advise screening FDRs of patients with UIA becauseall identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. Alonger follow-up should determine the risk of aneurysm growth requiring preventive treatment. Show less
Background and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We... Show moreBackground and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We investigated whetheraddition of these factors would improve the performance of prediction models for the risk ofstroke in women younger than 50 years.MethodsWe used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20–49 years without a history of cardiovasculardisease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportionalhazards models to predict stroke risk were developed, including traditional cardiovascularfactors, and compared with models that additionally included female-specific and psychosocialfactors. We compared the risk models using the c-statistic and slope of the calibration curve at afollow-up of 10 years. We developed an age-specific stroke risk prediction tool that may helpcommunicating the risk of stroke in clinical practice.ResultsWe included 409,026 women with a total of 3,990,185 person-years of follow-up. Strokeoccurred in 2,751 women (incidence rate 6.9 [95% CI 6.6–7.2] per 10,000 person-years).Models with only traditional cardiovascular factors performed poorly to moderately in all agegroups: 20–29 years: c-statistic: 0.617 (95% CI 0.592–0.639); 30–39 years: c-statistic: 0.615(95% CI 0.596–0.634); and 40–49 years: c-statistic: 0.585 (95% CI 0.573–0.597). After addingthe female-specific and psychosocial risk factors to the reference models, the model discrimi-nation increased moderately, especially in the age groups 30–39 (Dc-statistic: 0.019) and 40–49years (Dc-statistic: 0.029) compared with the reference models, respectively.DiscussionThe addition of female-specific factors and psychosocial risk factors improves the discrimina-tory performance of prediction models for stroke in women younger than 50 years. Show less
Broos, J.Y.; Loonstra, F.C.; Ruiter, L.R.J. de; Gouda, M.; Fung, W.H.; Schoonheim, M.M.; ... ; Kooij, G. 2023
Background and ObjectivesExcessive activation of certain lipid mediator (LM) pathways plays a role in the complexpathogenesis of multiple sclerosis (MS). However, the relationship between bioactive... Show moreBackground and ObjectivesExcessive activation of certain lipid mediator (LM) pathways plays a role in the complexpathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs anddifferent aspects of CNS-related pathophysiologic processes remains largely unknown.Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glialfibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients withMS (PwMS) and healthy controls (HCs).MethodsA targeted high-performance liquid chromatography-tandem mass spectrometry approach was usedon plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-basedcohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs werecompared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability(Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates wereincluded in a backward multivariate regression model to identify which LMs best related to disability.ResultsThe study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patientswith progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differedfrom those of patients with RRMS and HCs, particularly patients with PMS showed elevatedlevels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid(HETE) (r = 0.24, p < 0.001) correlated (average r = 0.2, p < 0.05) with clinical and biochemicalparameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lowertotal brain (r = −0.24, p = 0.04) and deep gray matter volumes (r = −0.27, p = 0.02) in patientswith PMS and higher lesion volume (r = 0.15, p = 0.03) in all PwMS.DiscussionIn PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability,biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicatethat, particularly, in patients with PMS, elevated levels of specific products of the AA pathway,such as 15-HETE, associate with neurodegenerative processes. Our findings highlight thepotential relevance of ω-6 LMs in the pathogenesis of MS. Show less
Background and ObjectivesTo investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the... Show moreBackground and ObjectivesTo investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study.MethodsAlbuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/μL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%).ResultsIn 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25–0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27–0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/μL in 1,005 patients (83%), 5–49 cells/μL in 200 patients (16%), and ≥50 cells/μL in 13 patients (1%).DiscussionACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/μL, is compatible with GBS after a thorough exclusion of alternative diagnoses. Show less
Background and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally compare treated patients with untreated patients with the same DMD... Show moreBackground and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally compare treated patients with untreated patients with the same DMD genotype class.This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligiblecontrols, increasing challenges for trial enrollment in this already rare disease. To evaluate thesuitability of genotypically unmatched controls in DMD, we quantified effects of genotype classon 1-year changes in motor function endpoints used in clinical trials.MethodsMore than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX,North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group),with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable,nonsense, and other mutations. Associations between genotype class and 1-year changes inNorth Star Ambulatory Assessment total score (DNSAA) and in 10-m walk/run velocity(D10MWR) were studied in each data source with and without adjustment for baselineprognostic factors.ResultsThe studied genotype classes accounted for approximately 2% of variation in DNSAA outcomesafter 12 months, whereas other prognostic factors explained >30% of variation in large datasources. Based on a meta-analysis across all data sources, pooled effect estimates for the studiedskip-amenable mutation classes were all small in magnitude (<2 units in DNSAA total score in1-year follow up), smaller than clinically important differences in NSAA, and were preciselyestimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. Show less
Meer, P.B. van der; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2023
Background and ObjectivesApproximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate... Show moreBackground and ObjectivesApproximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate whether levetiracetam combined with valproic acid and clobazam (LEV + VPA + CLB), a frequently prescribed triple therapy, has favorable effectiveness compared with other triple therapy combinations in patients with glioma.MethodsThis was a multicenter retrospective observational cohort study. The primary outcome was the cumulative incidence of time to treatment failure for any reason, from the start of ASM triple therapy treatment. The secondary outcomes included cumulative incidences of the following: (1) time to treatment failure due to uncontrolled seizures; (2) time to treatment failure due to adverse effects; and (3) time to recurrent seizures. Patients were followed up for a maximum duration of 36 months.ResultsOf 1,435 patients in the original cohort, 90 patients received ASM triple therapy after second-line ASM treatment failure due to uncontrolled seizures. LEV + VPA + CLB was prescribed to 48% (43/90) and other ASM triple therapy to 52% (47/90) of patients. The cumulative incidence of treatment failure for any reason of LEV + VPA + CLB did not statistically significantly differ from that of other ASM triple therapy combinations (12 months: 47% [95% CI 31%–62%] vs 42% [95% CI 27%–56%], p = 0.892). No statistically significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95% CI 4%–25%] vs 18% [95% CI 8%–30%], p = 0.445), adverse effects (12 months: 22% [95% CI 11%–36%] vs 15% [95% CI 7%–27%], p = 0.446), or recurrent seizures (1 month: 65% [95% CI 48%–78%] vs 63% [95% CI 47%–75%], p = 0.911) were found. Show less
Velde, N.M. van de; Koeks, Z.; Signorelli, M.; Verwey, N.; Overzier, M.; Bakker, J.A.; ... ; Niks, E.H. 2023
Background and Objectives: The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3... Show moreBackground and Objectives: The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD. Methods: We quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinine(ratio) (Cr/Crn) using liquid chromatography-tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models. Results: Thirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = -0.869 to -0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age (p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = -0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT. Discussion: Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers. Show less
Velde, N.M. van de; Koeks, Z.; Signorelli, M.; Verwey, N.; Overzier, M.; Bakker, J.A.; ... ; Niks, E.H. 2023
Background and ObjectivesThe slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3... Show moreBackground and ObjectivesThe slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD.MethodsWe quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography–tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models.ResultsThirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = −0.869 to −0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age (p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = −0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT.DiscussionBoth Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers. Show less
Velde, N.M. van de; Koeks, Z.; Signorelli, M.; Verwey, N.; Overzier, M.; Bakker, J.A.; ... ; Niks, E.H. 2023
Background and Objectives The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3... Show moreBackground and Objectives The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD.Methods We quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography–tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models.Results Thirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = −0.869 to −0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age (p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = −0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT.Discussion Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers. Show less
Background and ObjectivesCauses of stroke in young adults differ from those in the elderly individuals, and in a larger percentage,no cause can be determined. To gain more insight into the etiology... Show moreBackground and ObjectivesCauses of stroke in young adults differ from those in the elderly individuals, and in a larger percentage,no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in theyoung population, we investigated whether trigger factors, such as short-lasting exposure to toxins orinfection, may play a role.MethodsPatients aged 18–49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17participating centers in the Netherlands completed a questionnaire about exposure to 9 potentialtrigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used toassess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologicsubgroups of ischemic stroke.ResultsOne thousand one hundred forty-six patients completed the questionnaire (1,043 patients withan ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, anincreased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5–2.8) and vigorousphysical exercise (RR 2.6, 95% CI 2.2–3.0), within 2 hours after sexual activity (RR 2.4, 95% CI1.6–3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7–4.9), and within 24 hours afterfever or flu-like disease (RR 14.1, 95% CI 10.5–31.2; RR 13.9, 95% CI 8.9–21.9). Four triggerfactors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of car-dioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic strokecombined and stroke with multiple causes, and none that of stroke due to small vessel disease.DiscussionWe identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, andflu-like disease as potential trigger factors for stroke in the young population and found differencesin the type and number of trigger factors associated with different etiologic subgroups of ischemicstroke. These findings might help in better understanding the pathophysiologic mechanisms of(cryptogenic) stroke in the young population. Show less
Background and ObjectivesIt is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the... Show moreBackground and ObjectivesIt is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD using normative brain volumetry software.MethodsPresymptomatic GRN, MAPT, and C9orf72 pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib (R) ND, which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared with reference centile curves based on a large population-derived sample of nondemented individuals (n = 4,951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age.ResultsThirty-four GRN, 8 MAPT, and 14 C9orf72 pathogenic variant carriers were included (mean age = 52.1, standard deviation = 7.2; 66% female). The mean follow-up duration of the study was 64 +/- 33 months (median = 52; range 13-108). GRN pathogenic variant carriers showed a faster decline than the reference centile curves for all brain areas, though relative volumes remained between the 5th and 75th percentiles between the ages of 45 and 70 years. In MAPT pathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45 years and showed a further decline between the ages 50 and 60 years. Temporal lobe volume started in the 50th percentile at age 45 years but showed fastest decline over time compared with other brain structures. Frontal, temporal, parietal, and cerebellar volume already started below the 5th percentile compared with the reference centile curves at age 45 years for C9orf72 pathogenic variant carriers, but there was minimal decline over time until the age of 60 years.DiscussionWe provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease tracking and staging biomarkers in genetic FTD. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response. Show less
Velde, N.M. van de; Koeks, Z.; Signorelli, M.; Verwey, N.; Overzier, M.; Bakker, J.A.; ... ; Niks, E.H. 2022
Diffuse infiltrating gliomas are the most common malignant brain tumors in adults. The 2021 World Health Organization classification for CNS tumors (CNS5 WHO) has significantly altered the rules... Show moreDiffuse infiltrating gliomas are the most common malignant brain tumors in adults. The 2021 World Health Organization classification for CNS tumors (CNS5 WHO) has significantly altered the rules for classification and grading of diffuse gliomas. Clinicians, including neurology residents and neurologists, will have to consider the changes that include the introduction of new tumor types, allotting established tumor types to other groups and substituting previously essential morphological features for additional molecular markers. For example, in the current classification, glioblastoma is defined as isocitrate dehydrogenase (IDH)-wildtype, grade 4. Whereas, a grade 4 IDH-mutated astrocytic glioma is referred to as astrocytoma, IDH-mutated, grade 4. In addition, potential targeted treatments, based on the underlying molecular alterations, have become therapeutic options for diffuse gliomas. For clinicians, it is important to know the rationale for why these options are only available for specific tumors. Owing to the emphasis of molecular markers in the CNS5 WHO classification, interpretation of a pathology report and understanding of its clinical implications can be challenging. This review describes the most important molecular alterations in glioma, summarizes the recent changes in the CNS5 WHO classification for glioma, and presents a stepwise approach for trainees and neurologists to decipher a glioma pathology report. Additional information is summarized in eTable 1 (links.lww.com/WNL/C324). Show less
Background and Objectives: Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies are approved as preventive treatment for migraine. Recent concerns have been raised after a... Show moreBackground and Objectives: Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies are approved as preventive treatment for migraine. Recent concerns have been raised after a retrospective analysis of postmarketing case reports of elevated blood pressure (BP) associated with erenumab. In this prospective follow-up study, we aimed to assess the safety regarding BP in a real-world setting. Methods: All people with migraine who were treated with erenumab and fremanezumab at the Leiden Headache Center between January 2019 and January 2021 were included. BP measurements were collected from baseline (T0) until 12 months of follow-up, with a 3-month interval (T1-T4). Mixed linear models were fitted with time as a fixed effect and the patient as a random effect. Results: Both systolic and diastolic BP were increased at all time points T1-T4 compared with T0 (p < 0.001). The maximum estimated increase in the mean systolic BP was 5.2 mm Hg (95% CI 3.1-7.5). The maximum estimated increase in the mean diastolic BP was 3.5 mm Hg (95% CI 2.0-4.9). In the erenumab group (n = 109), both systolic and diastolic BP were increased at all time points compared with T0 (all p < 0.001). For fremanezumab (n = 87), systolic but not diastolic BP was increased compared with T0 at T1 (p = 0.006) and T2 (p = 0.004). Four patients (3.7%) with normal BP at T0 required antihypertensive treatment after erenumab was started. Discussion: The mean systolic and diastolic BP increased after anti-CGRP (receptor) antibodies were started. The majority of patients remained within the normal BP limits, but some patients required antihypertensive treatment. Physicians should be aware that people with migraine may be at risk of developing hypertension when treated with anti-CGRP (receptor) antibodies, and this should be added to (inter)national treatment guidelines. Classification of Evidence: This study provides Class III evidence that anti-CGRP (receptor) antibodies increase BP when used to treat patients with migraine. Show less
Algra, A.M.; Greving, J.P.; Wermer, M.J.H.; Walderveen, M.A.A. van; Schaaf, I.C. van der; Zwan, A. van der; ... ; Vergouwen, M.D.I. 2022
Background and Objectives In counseling patients with an unruptured intracranial aneurysm (UIA), quality of life (QoL) outcomes are important for informed decision making. We evaluated QoL outcomes... Show moreBackground and Objectives In counseling patients with an unruptured intracranial aneurysm (UIA), quality of life (QoL) outcomes are important for informed decision making. We evaluated QoL outcomes in patients with and without preventive aneurysm occlusion at multiple time points during the first year after UIA diagnosis and studied predictors of QoL outcomes. Methods We performed a prospective cohort study in patients aged >= 18 years with a newly diagnosed UIA in 2 tertiary referral centers in the Netherlands between 2017 and 2019. Patients were sent QoL questionnaires at 7 (aneurysm occlusion) or 5 (no occlusion) moments during the first year after diagnosis. We collected baseline data on patient and aneurysm characteristics, passive coping style (Utrecht Coping List), occlusion modality, and neurologic complications. We assessed health-related QoL (HRQoL) with the EuroQol 5 dimensions (EQ-5D), emotional functioning with the Hospital Anxiety and Depression Scale (HADS), and restrictions in daily activities with the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P). We used a linear mixed-effects model to assess the course of QoL over time and to explore predictors of QoL outcomes. Results Of 153 eligible patients, 99 (65%) participated, of whom 30/99 (30%) underwent preventive occlusion. Patients undergoing occlusion reported higher baseline levels of passive coping, anxiety and depression, and restrictions than patients without occlusion. During recovery after occlusion, patients reported more restrictions compared with baseline (adjusted USER-P decrease 1 month post occlusion: -12.8 [95% CI -23.8 to -1.9]). HRQoL and emotional functioning gradually improved after occlusion (EQ-5D increase at 1 year: 8.6 [95% CI 0.1-17.0] and HADS decrease at 1 year: -5.4 [95% CI -9.4 to -1.5]). In patients without occlusion, the largest HRQoL improvement occurred directly after visiting the outpatient aneurysm clinic (EQ-5D increase: 9.2 [95% CI 5.5-12.8]). At 1 year, QoL outcomes were comparable in patients with and without occlusion. Factors associated with worse QoL outcomes were a passive coping style in all patients, complications in patients with occlusion, and higher rupture risks in patients without occlusion. Discussion After UIA diagnosis, QoL improves gradually after preventive occlusion and directly after counseling at the outpatient clinic in patients without occlusion, resulting in comparable 1-year QoL outcomes. A passive coping style is an important predictor of poor QoL outcomes in all patients with UIA. Show less
Vezyroglou, A.; Akilapa, R.; Barwick, K.; Koene, S.; Brownstein, C.A.; Holder-Espinasse, M.; ... ; Balasubramanian, M. 2022
Background and Objectives ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating... Show moreBackground and Objectives ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021. Results Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. Discussion Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone. Show less
Napierkowski, I.; Lorenz-Meyer, I.; Hille, A.; Ebinger, M.; Freitag, E.; Harmel, P.; ... ; Berlin-SPecific Acute Treatment Ischemic or hAemorrhagic Stroke With Long Term Follow-up 2022
Background and Objectives: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly... Show moreBackground and Objectives: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly by underrepresenting patients with neurologic communication deficits and impaired capacity to consent. Many patients who are initially unable to give consentmay be willing to do so after recovery. Informing patients on study purposes and procedures with offering them the option of nonparticipation but not requesting explicit consent is called "opt-out" approach. We investigated whether an opt-out strategy yields meaningful follow-up rates in an acute stroke registry with an embedded controlled study. Methods: The citywide Berlin-SPecific Acute Treatment in Ischemic or hAemorrhagic Stroke With Long Term Follow-up (B-SPATIAL) registry was designed to provide reliable information on process indicators and outcomes of specific acute stroke treatments to inform health care providers about quality of care and best practice strategies including the effects of a mobile stroke unit implementation. Because this information was regarded of high public interest, Berlin data protection authorities permitted data sampling without prior informed consent, using instead follow-up assessment on an "opt-out" basis. Patients were included if they had neurologic symptoms at ambulance or hospital arrival within 6 hours of onset and had a final diagnosis of stroke or TIA. Information on data collection and outcome assessment was sent by letter to patients 1 month before follow-up. Results: From February 1, 2017, to January 31, 2020, a total of 10,597 patients were assessed. Thirty-one (0.3%) patients declined any data use, whereas 578 (5.5%) opted out of follow-up assessment. Of those not opting out (n = 9,988), functional outcome (modified Rankin Scale) was collected in 8,330 patients (83.4%) and vital status in 9,741 patients (97.5%). We received no complaints regarding data collection procedures. Discussion: Opt-out-based follow-up collection offers a way to achieve high follow-up rates along with respecting patients' preferences. Show less
Meer, P.B. van der; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2022
Background and Objectives: About 30% of patients with glioma need an add-on antiseizure medication (ASM) due to uncontrolled seizures on ASM monotherapy. This study aimed to determine whether... Show moreBackground and Objectives: About 30% of patients with glioma need an add-on antiseizure medication (ASM) due to uncontrolled seizures on ASM monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV + VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in patients with glioma. Methods: In this multicenter retrospective observational cohort study, treatment failure (i.e., replacement by, addition of, or withdrawal of an ASM) for any reason was the primary outcome. Secondary outcomes included (1) treatment failure due to uncontrolled seizures and (2) treatment failure due to adverse effects. Time to treatment failure was estimated from the moment of ASM duotherapy initiation. Multivariable cause-specific Cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months. Results: A total of 1,435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received ASM duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV + VPA was prescribed in 66% (236/355) and other ASM duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy vs LEV + VPA had a higher risk of treatment failure for any reason (cause-specific adjusted hazard ratio [aHR] 1.50 [95% CI 1.07-2.12], p = 0.020), due to uncontrolled seizures (cause-specific aHR 1.73 [95% CI 1.10-2.73], p = 0.018), but not due to adverse effects (cause-specific aHR 0.88 [95% CI 0.47-1.67], p = 0.703). Discussion: This observational cohort study suggests that LEV + VPA has better efficacy than other ASM combinations. Similar toxicities were experienced in the 2 groups. Classification of Evidence: This study provides Class III evidence that for patients with glioma with uncontrolled seizures on ASM monotherapy, LEV + VPA has better efficacy than other ASM combinations. Show less
Meer, P.B. van der; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2022
Background and Objectives: About 30% of patients with glioma need an add-on antiseizure medication (ASM) due to uncontrolled seizures on ASM monotherapy. This study aimed to determine whether... Show moreBackground and Objectives: About 30% of patients with glioma need an add-on antiseizure medication (ASM) due to uncontrolled seizures on ASM monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV + VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in patients with glioma. Methods: In this multicenter retrospective observational cohort study, treatment failure (i.e., replacement by, addition of, or withdrawal of an ASM) for any reason was the primary outcome. Secondary outcomes included (1) treatment failure due to uncontrolled seizures and (2) treatment failure due to adverse effects. Time to treatment failure was estimated from the moment of ASM duotherapy initiation. Multivariable cause-specific Cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months. Results A total of 1,435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received ASM duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV + VPA was prescribed in 66% (236/355) and other ASM duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy vs LEV + VPA had a higher risk of treatment failure for any reason (cause-specific adjusted hazard ratio [aHR] 1.50 [95% CI 1.07-2.12], p = 0.020), due to uncontrolled seizures (cause-specific aHR 1.73 [95% CI 1.10-2.73], p = 0.018), but not due to adverse effects (cause-specific aHR 0.88 [95% CI 0.47-1.67], p = 0.703). Discussion: This observational cohort study suggests that LEV + VPA has better efficacy than other ASM combinations. Similar toxicities were experienced in the 2 groups. Classification of Evidence This study provides Class III evidence that for patients with glioma with uncontrolled seizures on ASM monotherapy, LEV + VPA has better efficacy than other ASM combinations. Show less
